Chitosan-Based Systems for Biopharmaceuticals E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1354

Veröffentlichungsjahr: 2012

Beschreibung

Chitosan is a linear polysaccharide commercially produced by thedeacetylation of chitin. It is non-toxic, biodegradable,biocompatible, and acts as a bioadhesive with otherwise unstablebiomolecules - making it a valuable component in the formulation ofbiopharmaceutical drugs. Chitosan-Based Systems for Biopharmaceuticals provides anextensive overview of the application of chitosan and itsderivatives in the development and optimisation ofbiopharmaceuticals. The book is divided in four different parts.Part I discusses general aspects of chitosan and its derivatives,with particular emphasis on issues related to the development ofbiopharmaceutical chitosan-based systems. Part II deals with theuse of chitosan and derivatives in the formulation and delivery ofbiopharmaceuticals, and focuses on the synergistic effects betweenchitosan and this particular subset of pharmaceuticals. Part IIIdiscusses specific applications of chitosan and its derivatives forbiopharmaceutical use. Finally, Part IV presents diverse viewpointson different issues such as regulatory, manufacturing andtoxicological requirements of chitosan and its derivatives relatedto the development of biopharmaceutical products, as well as theirpatent status, and clinical application and potential. Topics covered include: * chemical and technological advances in chitins and chitosansuseful for the formulation of biopharmaceuticals * physical properties of chitosan and derivatives in sol and gelstates * absorption promotion properties of chitosan andderivatives * biocompatibility and biodegradation of chitosan andderivatives * biological and pharmacological activity of chitosan andderivatives * biological, chemical and physical compatibility of chitosan andbiopharmaceuticals * approaches for functional modification or crosslinking ofchitosan * use of chitosan and derivatives in conventionalbiopharmaceutical dosage forms * manufacture techniques of chitosan-based microparticles andnanoparticles for biopharmaceuticals * chitosan and derivatives for biopharmaceutical use:mucoadhesive properties * chitosan-based systems for mucosal delivery ofbiopharmaceuticals * chitosan-based delivery systems for mucosal vaccination * chitosan-based nanoparticulates for oral delivery ofbiopharmaceuticals * chitosan-based systems for ocular delivery ofbiopharmaceuticals * chemical modification of chitosan for delivery of DNA andsiRNA * target-specific chitosan-based nanoparticle systems for nucleicacid delivery * functional PEGylated chitosan systems forbiopharmaceuticals * stimuli-sensitive chitosan-based systems forbiopharmaceuticals * chitosan copolymers for biopharmaceuticals * application of chitosan for anti-cancer biopharmaceuticaldelivery * chitosan-based biopharmaceuticals scaffolds in tissueengineering and regenerative medicine * wound healing properties of chitosan and its use in wounddressing biopharmaceuticals * toxicological properties of chitosan and derivatives forbiopharmaceutical applications * regulatory status of chitosan and derivatives * patentability and intellectual property issues * quality control and good manufacturing practice * preclinical and clinical use of chitosan and derivatives forbiopharmaceuticals Chitosan-Based Systems for Biopharmaceuticals is animportant compendium of fundamental concepts, practical tools andapplications of chitosan-based biopharmaceuticals for researchersin academia and industry working in drug formulation and delivery,biopharmaceuticals, medicinal chemistry, pharmacy, bioengineeringand new materials development.

Leseprobe

Contents

Cover

Title Page

Copyright

List of Contributors

Foreword

Preface

References

Acknowledgments

Part 1: General Aspects of Chitosan

Chapter 1: Chemical and Technological Advances in Chitins and Chitosans Useful for the Formulation of Biopharmaceuticals

1.1 Introduction

1.2 Safety of Chitins and Chitosans

1.3 Ionic Liquids: New Solvents and Reaction Media

1.4 Chitin and Chitosan Nanofibrils

1.5 Electrospun Nanofibers

1.6 Polyelectrolyte Complexes and Mucoadhesion

1.7 Conclusions and Future Perspectives

Acknowledgments

References

Chapter 2: Physical Properties of Chitosan and Derivatives in Sol and Gel States

2.1 Introduction

2.2 Chitin

2.3 Chitosan

2.4 Conclusions and Future Perspectives

References

Chapter 3: Absorption Promotion Properties of Chitosan and Derivatives

3.1 Introduction

3.2 Effect of Chitosan on the Intestinal Absorption of Poorly Absorbable Drugs

3.3 Effect of Chitosan Derivatives on the Intestinal Absorption of Poorly Absorbable Drugs

3.4 Effect of Chitosan Oligomers on the Intestinal Absorption of Poorly Absorbable Drugs

3.5 Colon-Specific Delivery of Insulin Using Chitosan Capsules

3.6 Conclusions and Future Perspectives

References

Chapter 4: Biocompatibility and Biodegradation of Chitosan and Derivatives

4.1 Introduction

4.2 Biocompatibility Evaluation of Chitosan and Derivatives

4.3 Biodegradation of Chitosan and Derivatives

4.4 Conclusions and Future Perspectives

References

Chapter 5: Biological and Pharmacological Activity of Chitosan and Derivatives

5.1 Introduction

5.2 Biological Activity

5.3 Chitosan's Usefulness in Therapy and Alternative Medicine

5.4 Conclusions and Future Perspectives

Acknowledgments

References

Further Reading

Chapter 6: Biological, Chemical, and Physical Compatibility of Chitosan and Biopharmaceuticals

6.1 Introduction

6.2 Structural Features of Chitosan and Its Derivatives

6.3 Biocompatibility for Chitosan and Its Derivatives

6.4 Biocompatibility of Photo-Cross-Linkable Chitosan Hydrogel

6.5 Physical and Chemical Compatibility of Chitosan and Its Derivatives

6.6 Conclusions and Future Perspectives

References

Chapter 7: Approaches for Functional Modification or Cross-Linking of Chitosan

7.1 Introduction

7.2 General Awareness of Chitosan Cross-Linking Methods

7.3 Modified Chitosan: Synthesis and Characterization

7.4 Applications of Modified Chitosan and Its Derivatives in Drug Delivery

7.5 Conclusions and Future Perspectives

Acknowledgments

References

Part 2: Biopharmaceuticals Formulation and Delivery Aspects Using Chitosan and Derivatives

Chapter 8: Use of Chitosan and Derivatives in Conventional Biopharmaceutical Dosage Forms Formulation

8.1 Introduction

8.2 Advantageous Properties of Chitosan and Its Derivatives

8.3 Oral Administration

8.4 Buccal Administration

8.5 Nasal Administration

8.6 Pulmonary Administration

8.7 Transdermal Administration

8.8 Conclusions and Future Perspectives

References

Chapter 9: Manufacture Techniques of Chitosan-Based Microparticles and Nanoparticles for Biopharmaceuticals

9.1 Introduction

9.2 Water-in-Oil Emulsion and Chemical Cross-linking

9.3 Drying Techniques

9.4 Ionic Cross-linking Methods

9.5 Coacervation and Precipitation Method

9.6 Direct Interaction between Chitosan and Biopharmaceuticals

9.7 Conclusions and Future Perspectives

References

Chapter 10: Chitosan and Derivatives for Biopharmaceutical Use: Mucoadhesive Properties

10.1 Introduction

10.2 Mucoadhesion

10.3 Chitosan and Its Derivatives

10.4 Biopharmaceutical Use of Chitosan and Its Derivatives

10.5 Conclusions and Future Perspectives

References

Chapter 11: Chitosan-Based Systems for Mucosal Delivery of Biopharmaceuticals

11.1 Introduction

11.2 Important Challenges for the Delivery of Biopharmaceuticals by Mucosal Routes

11.3 Interest in Chitosan for Mucosal Delivery of Biopharmaceuticals

11.4 Chitosan-Based Delivery Nanosystems for Mucosal Delivery of Biopharmaceuticals

11.5 Conclusions and Future Perspectives

Acknowledgments

References

Chapter 12: Chitosan-Based Delivery Systems for Mucosal Vaccination

12.1 Introduction

12.2 Adjuvant Properties of Chitosan

12.3 Chitosan in the Delivery of Protein and Subunit Vaccines

12.4 Chitosan-Based Formulations of DNA Vaccines

12.5 Vaccine Formulations Using Chitosan in Combination with Other Polymers

12.6 Chitosan Derivatives in Vaccine Carrier Design

12.7 Conclusions and Future Perspectives

References

Chapter 13: Chitosan-Based Nanoparticulates for Oral Delivery of Biopharmaceuticals

13.1 Introduction

13.2 Challenges on the Oral Delivery of Therapeutic Proteins

13.3 Challenges on the Oral Delivery of Genetic Material

13.4 Role of Chitosan in the Protection of Biopharmaceuticals in the Gastrointestinal Tract

13.5 Chitosan-Based Nanoparticles for Oral Delivery of Therapeutic Proteins

13.6 Chitosan-Based Nanoparticles for Oral Delivery of Genetic Material

13.7 Conclusions and Future Perspectives

Acknowledgments

References

Chapter 14: Chitosan-Based Systems for Ocular Delivery of Biopharmaceuticals

14.1 Introduction

14.2 Ocular Delivery of Biopharmaceuticals

14.3 Chitosan: A Suitable Biomaterial for Ocular Therapeutics

14.4 Chitosan-Based Systems for Ocular Delivery of Biomacromolecules

14.5 Toxicological and Compatibility Aspects of Chitosan-Based Ocular Systems

14.6 Conclusions and Future Perspectives

References

Chapter 15: Chemical Modification of Chitosan for Delivery of DNA and siRNA

15.1 Introduction

15.2 Hydrophilic Modification

15.3 Hydrophobic Modification

15.4 Specific Ligand Modification

15.5 pH-Sensitive Modification

15.6 Conclusions and Future Perspectives

Acknowledgment

References

Part 3: Advanced Application of Chitosan and Derivatives for Biopharmaceuticals

Chapter 16: Target-Specific Chitosan-Based Nanoparticle Systems for Nucleic Acid Delivery

16.1 Introduction

16.2 Chitosan-Based Nanoparticle Delivery Systems

16.3 Illustrative Examples of DNA Vaccine Delivery

16.4 Illustrative Examples of Nucleic Acid Delivery Systems for Cancer Therapy

16.5 Illustrative Examples of Nucleic Acid Delivery Systems for Anti-Inflammatory Therapy

16.6 Conclusions and Future Perspectives

References

Chapter 17: Functional PEGylated Chitosan Systems for Biopharmaceuticals

17.1 Introduction

17.2 PEGylated Chitosan for the Delivery of Proteins and Peptides

17.3 PEGylated Chitosan for Delivery of Nucleic Acids

17.4 PEGylated Chitosan for Delivery of Other Macromolecular Biopharmaceuticals

17.5 PEGylated Chitosan Used for Cellular Scaffolds

17.6 Conclusions and Future Perspectives

References

Chapter 18: Stimuli-Sensitive Chitosan-Based Systems for Biopharmaceuticals

18.1 Introduction

18.2 pH-Sensitive Chitosan-Based Systems

18.3 Thermosensitive Chitosan-Based Systems

18.4 pH-Sensitive and Thermosensitive Chitosan-Based Systems

18.5 pH- and Ionic-Sensitive Chitosan-Based Systems

18.6 Photo-Sensitive Chitosan-Based Systems

18.7 Electrical-Sensitive Chitosan-Based Systems

18.8 Magnetic-Sensitive Chitosan-Based Systems

18.9 Chemical Substance-Sensitive Chitosan-Based Systems

18.10 Conclusions and Future Perspectives

References

Chapter 19: Chitosan Copolymers for Biopharmaceuticals

19.1 Introduction

19.2 Chitosan-g-Poly(Ethylene Glycol)

19.3 Chitosan-g-Polyethylenimine

19.4 Other Copolymers of Chitosan

19.5 Copolymers of Chitosan with Promising Applications

19.6 Conclusions and Future Perspectives

References

Chapter 20: Application of Chitosan for Anticancer Biopharmaceutical Delivery

20.1 Introduction

20.2 Chitosan and Cancer: Intrinsic Antitumor Activity of the Polymer Itself

20.3 Chitosan Formulations Developed for Classic Anticancer Drugs

20.4 Biopharmaceuticals Delivered by Chitosan Preparations

20.5 Active Targeting Strategies and Multifunctional Chitosan Formulations

20.6 Conclusions and Future Perspectives

References

Chapter 21: Chitosan-Based Biopharmaceutical Scaffolds in Tissue Engineering and Regenerative Medicine

21.1 Introduction

21.2 Fabrication of Chitosan-Based Biopharmaceuticals Scaffolds

21.3 Applications of Chitosan-Based Biopharmaceutical Scaffolds in Tissue Engineering and Regenerative Medicine

21.4 Future Trends: Regenerative Engineering

21.5 Conclusions and Future Perspectives

Acknowledgments

References

Chapter 22: Wound-Healing Properties of Chitosan and Its Use in Wound Dressing Biopharmaceuticals

22.1 Introduction

22.2 Brief Review of Wound Repair

22.3 Wound-Healing Effects of Chitosan

22.4 Chitosan for Wound Therapeutics Delivery

22.5 Conclusions and Future Perspectives

Acknowledgments

References

Part 4: Regulatory Status, Toxicological Issues, and Clinical Perspectives

Chapter 23: Toxicological Properties of Chitosan and Derivatives for Biopharmaceutical Applications

23.1 Introduction

23.2 In Vitro Toxicity of Chitosan and Derivatives

23.3 In Vivo Toxicity of Chitosan and Derivatives

23.4 Conclusions and Future Perspectives

References

Chapter 24: Regulatory Status of Chitosan and Derivatives

24.1 Introduction

24.2 Source

24.3 Characterization

24.4 Purity

24.5 Applications of Advanced Uses of Chitosan

24.6 Regulatory Considerations for Chitosan and Chitosan Derivatives in the European Union, and Medical Devices or Combination Products with Medical Device (CDRH) Lead

24.7 Regulatory Pathways

24.8 Chitosan Medical Products: US Regulatory Review Processes for Medical Devices or Combination Products with CDRH Lead

24.9 Chitosan Wound Dressings

24.10 The European Regulatory System: The European Medicines Agency (EMA) and European Directorate for the Quality of Medicines (EDQM)

24.11 Further Regulatory Considerations

24.12 Conclusions and Future Perspectives

Acknowledgments

24.14 Disclaimer

References

Chapter 25: Patentability and Intellectual Property Issues Related to Chitosan-Based Biopharmaceutical Products

25.1 Introduction

25.2 Setting the Scene: The Role of Chitosan as a Pharmaceutical Excipient

25.3 Addressing the Drivers for Scientific Progress on Chitosan: Innovation and Inventability

25.4 Conclusions and Future Perspectives

References

Chapter 26: Quality Control and Good Manufacturing Practice (GMP) for Chitosan-Based Biopharmaceutical Products

26.1 Introduction

26.2 Regulatory Requirements for Production

26.3 Manufacturing GMP: Fundamental Considerations

26.4 Requirements for Rooms, Personnel, and Equipment

26.5 Qualification and Validation

26.6 Quality Control

26.7 Monitoring and Maintenance of a GMP System

26.8 Conclusions and Future Perspectives

References

Chapter 27: Preclinical and Clinical Use of Chitosan and Derivatives for Biopharmaceuticals: From Preclinical Research to the Bedside

27.1 Introduction

27.2 Chitosan as a Parenteral (Subcutaneous) Vaccine Platform

27.3 Chitosan as an Immunotherapeutic Platform

27.4 Conclusions and Future Perspectives

References

Index

This edition first published 2012

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Library of Congress Cataloging-in-Publication Data

Chitosan-based systems for biopharmaceuticals : delivery, targeting, and polymer therapeutics / edited by Bruno Sarmento, José das Neves.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-0-470-97832-0 (cloth) – ISBN 978-1-119-96296-0 (ePDF) – ISBN 978-1-119-96297-7 (oBook) – ISBN 978-1-119-96407-0 (ePub) – ISBN 978-1-119-96408-7 (eMobi)

I. Sarmento, Bruno. II. das Neves, José, 1978-

[DNLM: 1. Biopharmaceutics. 2. Chitosan–therapeutic use. 3. Biopolymers–therapeutic use. 4. Drug Carriers–therapeutic use. QU 83]

615.1'9–dc23

2011037452

Print ISBN: 9780470978320

List of Contributors

Wafa I. Abdel-Fattah, Biomaterials Department, National Research Centre, Cairo, Egypt

Toshihiro Akaike, Department of Biomolecular Engineering, Tokyo Institute of Technology, Yokohama, Japan

Marlene Almeida, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal

Sonia Al-Qadi, Department of Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Faculty of Pharmacy, Santiago de Compostela, Spain

Mansoor Amiji, Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA

Fernanda Andrade, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

A. Anitha, Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, India

Filipa Antunes, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

Sambasiva R. Arepalli, Center for Devices and Radiological Health, United States Food and Drug Administration, Silver Spring, MD, USA

Pedro Barrocas, Laboratory of Pharmaceutical Development, R&D Department, Bial - Portela & C.a, S.A., S. Mamede do Coronado, Portugal

Andreas Bernkop-Schnürch, Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innsbruck, Austria

M. Cristina Bonferoni, Department of Drug Sciences, School of Pharmacy, University of Pavia, Pavia, Italy

Gerrit Borchard, School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland

Joel D. Bumgardner, Department of Biomedical Engineering, University of Memphis, TN, USA

Carla M. Caramella, Department of Drug Sciences, School of Pharmacy, University of Pavia, Pavia, Italy

Rui Cerdeira, Laboratory of Pharmaceutical Development, R&D Department, Bial - Portela & C.a, S.A., S. Mamede do Coronado, Portugal

Chong-Su Cho, Department of Agricultural Biotechnology, and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea

Hee-Jeong Cho, College of Pharmacy, Seoul National University, Seoul, South Korea

Myung-Haing Cho, Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea

Yun-Jaie Choi, Department of Agricultural Biotechnology, and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea

Teresa Cunha, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal

Tianhong Dai, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA

Department of Dermatology, Harvard Medical School, Boston, MA, USA

José das Neves, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

Meng Deng, Department of Orthopaedic Surgery, University of Connecticut, Farmington, CT, USA

Gustavo Dias, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal

Michael Dornish, FMC BioPolymer AS/NovaMatrix, Sandvika, Norway

Farnaz Esmaeili, King's College London, Pharmaceutical Science Division, London, United Kingdom

Jonathan Fallon, Laboratory of Tumor Immunology and Biology, National Cancer Institute, CCR, National Institutes of Health, Bethesda, MD, USA

Eduardo Fernandez-Megia, Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain

Franca Ferrari, Department of Drug Sciences, School of Pharmacy, University of Pavia, Pavia, Italy

Masanori Fujita, Research Institute, National Defense Medical College, Saitama, Japan

Qingyu Gao, Institute of Fine Chemical and Engineering, Henan University, Kaifeng, People's Republic of China

Rogério Gaspar, Nanomedicine and Drug Delivery Systems Group, iMed.UL– Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

John W. Greiner, Laboratory of Tumor Immunology and Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA

Ana Grenha, Centre for Molecular and Structural Biomedicine, Institute for Biotechnology and Bioengineering, University of Algarve, Faro, Portugal

Maika Gulich, Heppe Medical Chitosan GmbH, Halle (Saale), Germany

Ding-Ding Guo, Department of Agricultural Biotechnology, and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea

Ahmad Sukari Halim, Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia

Michael R. Hamblin, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA

Department of Dermatology, Harvard Medical School, Boston, MA, USA

Harvard–MIT Division of Health Sciences and Technology, Cambridge, MA, USA

Hidemi Hattori, Research Institute, National Defense Medical College, Saitama, Japan

Michael Heffernan, Laboratory of Tumor Immunology and Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA

Simon Heuking, Vaccine Formulation Laboratory, Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

Ying-Ying Huang, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA

Department of Dermatology, Harvard Medical School, Boston, MA, USA

Aesthetic and Plastic Center of Guangxi Medical University, Nanning, China

Masayuki Ishihara, Research Institute, National Defense Medical College, Saitama, Japan

Shardool Jain, Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA

Rangasamy Jayakumar, Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, India

Hu-Lin Jiang, Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea

Tao Jiang, Zimmer Orthobiologics, Inc., Austin, TX, USA

Yasuhiro Kanatani, Department of Policy Science, National Institute of Public Health, Saitama, Japan

David S. Kaplan, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA

Thomas J. Kean, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA

Lim Chin Keong, Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia

Goen Kim, College of Pharmacy, Seoul National University, Seoul, South Korea

You-Kyoung Kim, Department of Agricultural Biotechnology, and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea

Satoko Kishimoto, Research Institute, National Defense Medical College, Saitama, Japan

Research Fellow of the Japan Society for Promotion of Science, Tokyo, Japan

Hyeok-Seung Kwon, College of Pharmacy, Seoul National University, Seoul, South Korea

Cato T. Laurencin, Department of Orthopedic Surgery, University of Connecticut, Farmington, CT, USA

Department of Chemical, Materials and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA

Claus-Michael Lehr, Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany

Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarland University, Saarbrücken, Germany

Katharina Leithner, Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innsbruck, Austria

Brigitta Loretz, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarland University, Saarbrücken, Germany

Riccardo A. A. Muzzarelli, Professor Emeritus of Enzymology, University of Ancona, Ancona, Italy

Shanti V. Nair, Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, India

Ramon Novoa-Carballal, Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain

Yu-Kyoung Oh, College of Pharmacy, Seoul National University, Seoul, South Korea

Rishi Paliwal, Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, M.P., India

Shivani Rai Paliwal, Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, M.P., India

Claudia Philippi, Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany

Ahmad Hazri Abdul Rashid, SIRIM, Environmental and Bioprocess Technology Centre, Shah Alam, Selangor, Malaysia

N. Sanoj Rejinold, Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, India

Carmen Remuñán-López, Department of Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Faculty of Pharmacy, Santiago de Compostela, Spain

Katja Richter, Heppe Medical Chitosan GmbH, Halle (Saale), Germany

Torsten Richter, Heppe Medical Chitosan GmbH, Halle (Saale), Germany

Ricardo Riguera, Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain

Marguerite Rinaudo, Centre de Recherches sur les Macromolécules Végétales (CERMAV), Centre National de la Recherche Scientifique, affiliated with Joseph Fourier University, Grenoble, France

Silvia Rossi, Department of Drug Sciences, School of Pharmacy, University of Pavia, Pavia, Italy

Giuseppina Sandri, Department of Drug Sciences, School of Pharmacy, University of Pavia, Pavia, Italy

Bárbara Santos, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal

Bruno Sarmento, Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

CICS, Department of Pharmaceutical Sciences, Instituto Superior de Ciências da Saúde–Norte, Gandra, Portugal

Ulrich F. Schaefer, Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany

Tyler G. St. Denis, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA

Columbia University, New York, NY, USA

Branca Teixeira, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal

Maya Thanou, Pharmaceutical Sciences Division, King's College London, London, United Kingdom

Teófilo Vasconcelos, Laboratory of Pharmaceutical Development, R&D Department, Bial - Portela & C.a, S.A., S. Mamede do Coronado, Portugal

Mafalda Videira, Nanomedicine and Drug Delivery Systems Group, iMed.UL– Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

Suresh P. Vyas, Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, M.P., India

Akira Yamamoto, Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan

Jinfang Yuan, Institute of Fine Chemical and Engineering, Henan University, Kaifeng, People's Republic of China

David A. Zaharoff, Laboratory of Tumor Immunology and Biology, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA

Biomedical Engineering Program, University of Arkansas, Fayetteville, AR, USA

Ismail Zainol, Chemistry Department, Faculty of Science and Mathematics, Universiti Pendidikan Sultan Idris, Tanjung Malim, Perak, Malaysia

Cuiping Zhai, Institute of Fine Chemical and Engineering, Henan University, Kaifeng, People's Republic of China

Foreword

The reading of the book Chitosan-Based Systems for Biopharmaceuticals: Delivery, Targeting and Polymer Therapeutics has given me great pleasure because it represents a nice illustration of the area of research to which I have dedicated an important part of my research career. It was in the early 1990s, working at MIT with Bob Langer on the encapsulation of proteins within poly(lactide-co-glycolide) (PLGA) microspheres, that I became conscious of the necessity of new biomaterials for the controlled delivery of delicate compounds, that is, biopharmaceuticals; biomaterials which would be friendly with the associated compounds; biomaterials which could be converted into nanoparticles using mild techniques; and biomaterials that could have a low price based on their wide availability in nature. Chitosan comes to my mind as a wonderful biomaterial fulfilling all these desirable properties. Our goal was to convert chitosan powders into nanoparticles using a procedure that would be adequate for the association of biopharmaceuticals. We were then the first authors reporting the ionotropic gelation technique for the association of proteins to chitosan nanoparticles in 1997. Now, it is amazing for me to see how the history of this biomaterial has evolved. We find thousands of articles and hundreds of patents using the keywords “chitosan nanoparticles.” It is, indeed, the biomaterial that has attracted the most significant research attention in the area of nanodrug delivery. As a consequence of this accumulated information, we got to know this unique material quite well. For example, we currently recognize how we can engineer this material in order to make it useful for a variety of interesting biomedical applications and, even more importantly, we can appreciate how this biomaterial is making its way to a final purpose: to provide us with new solutions for improving our health and quality of life.

This book will be of great value to those readers who want to know about chitosan from the perspective of its potential for the delivery of biopharmaceuticals. Following an introductory section, the book is divided in three major parts. The first part is about the general properties of chitosan, with emphasis on the physical–chemical properties that are critical for processing it into adequate delivery systems and also on those of relevance for its use as a biomaterial for human use (biocompatibility and biodegradability). In addition, this part presents the inherent biological properties of chitosan, its behavioral mechanism of action upon contact with living cells and tissues, and the way it interacts with drugs and more precisely with delicate biomolecules such as peptides, proteins, antigens, and nucleic acid-based biocompounds. This part ends by presenting the possibility of chemically modifying chitosan in order to further extend the properties and functionalities of chitosan with regard to its use for the delivery of biopharmaceuticals.

In the second part of the book, the reader will find a great display of the possibilities of chitosan being processed into different pharmaceutical forms, starting by conventional dosage forms and continuing to micro- and nanoparticles. This part logically focuses on the special mucoadhesive properties of chitosan and, thus, on its potential for mucosal drug and vaccine delivery.

The third part is particularly illustrative of the degree of chitosan evolution as a biomaterial. It presents various ways to chemically modify and engineer chitosan in order to make it attractive for a variety of interesting applications, including wound dressing, targeted drug delivery, tissue engineering, and regenerative medicine.

The fourth and final section is without a doubt the most critical one for those who want to know where we stand on the prospects of chitosan as a biomaterial for drug delivery. This section complements the first one regarding the toxicological properties of chitosan under the perspective of the regulatory path and presents the quality control and good manufacturing practice required for chitosan-derived products. Most significantly, this part covers the amazing information available on chitosan patents and the patentability of chitosan-based biopharmaceutical products, this one being one of the most important applications of chitosan.

Overall, the book presents, in a didactic and well-structured form, critical information for readers interested in the delivery of biopharmaceuticals. It would also be of great benefit for researchers attempting to design, produce, and characterize new biomaterials. It would, of course, also be of interest for any student or researcher interested in the growing field of nanodrug delivery.

María José AlonsoProfessor of Biopharmacy and Pharmaceutical TechnologyUniversity of Santiago de Compostela (USC), Spain

Preface

Bruno Sarmento1,2 and José das Neves1

1Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

2CICS, Department of Pharmaceutical Sciences, Instituto Superior de Ciências da Saúde–Norte, Gandra, Portugal

Since the market launch in 1982 of the first recombinant “human” insulin (Humulin®, Eli Lilly, Indianapolis, IN, United States), biopharmaceutical medicinal products have seen a steady rise (with particular boosting in recent years) as important tools of modern therapeutics. With an estimated global market of over $US 167 billion by 2015 [1], biopharmaceuticals are currently widely recognized as highly effective molecules in the management of many metabolic, oncologic, and infectious diseases, as well as in the prevention and in vivo diagnosis of such diseases. This particular class of pharmaceuticals is quite heterogeneous and not always clearly defined, comprising different active biological molecules of different complexity such as proteins, peptides, and nucleic acids, among others, which are of biological origin and/or manufactured by biotechnological techniques, usually involving living organisms, cells, or their active components [2]. However, unfavorable physical–chemical properties, poor stability, low permeability, and unsuitable biodistribution of biopharmaceuticals pose important challenges for their adequate pharmaceutical formulation and delivery, and thus their use in therapy. In particular, the challenges in developing adequate materials and systems that allow the use of biopharmaceuticals in daily life are huge. Among the wide variety of proposed solutions for advancing the field [3, 4], delivery systems based on chitosan and derivatives have deserved recent singular attention.

The history of chitosan dates back to 1859, when French physiologist Charles Rouget (1824–1904) described the deacetylation of chitin by means of its boiling in the presence of concentrated potassium hydroxide [5]. Immediately, he recognized that the newly obtained product was soluble in acidic solutions, contrasting with the water-insoluble nature of native chitin, thus opening new possibilities for its use. However, it wasn't until 35 years later that the modified chitin received the name “chitosan”, which has been attributed to the German physiologist and chemist Felix Hoppe-Seyler (1825–1895) [6]. Nearly one century went by until this modified natural polymer started receiving enough attention as a useful material to be used in the design of drug products [7–9]. Over the years, the study of chitosan revealed that it exhibits several favorable biological properties, such as biocompatibility, biodegradability, low toxicity, and mucoadhesiveness, thus making this polymer a promising candidate for the formulation of biopharmaceuticals. More than a simple excipient for the design of conventional pharmaceutical dosage forms, the development of novel biopharmaceutical delivery systems based on chitosan is a rising subject irrespective of the intended route of administration.

In the present book, renowned experts and researchers from academia, industry, and regulatory bodies provide a concise and up-to-date overview of different issues regarding the application of chitosan and its derivatives for the development and optimization of biopharmaceutical medicinal products. The book is divided in four different parts. Part One discusses general aspects of chitosan and derivatives, with particular emphasis on issues related to the development of biopharmaceutical chitosan-based systems, comprising a useful background for the following chapters. Part Two deals with the use of chitosan and derivatives in the formulation and delivery of biopharmaceuticals, and focuses on the synergistic effects between chitosan and this particular subset of pharmaceuticals. Further, Part Three continues and complements the previous part by discussing in detail specific applications of chitosan and/or some particular derivatives for biopharmaceutical use. Finally, Part Four presents diverse viewpoints on different issues such as the regulatory, manufacturing, and toxicological requirements of chitosan and its derivatives related to the development of biopharmaceutical products, as well as their patent status and their clinical application and potential.

We expect this book to provide scientists and researchers in the fields of drug delivery, material science, medical science, and bioengineering, as well as professionals in the pharmaceutical, biotechnology, and healthcare industries, with an important compendium of fundamental concepts and practical tools for their daily activities. Also, the broad emphasis on different regulatory issues may turn this book into a relevant starting point for discussion among worldwide regulatory bodies, drug policymakers, and biopharmaceutical companies in pursuing suitable biopharmaceutical products based on chitosan and its derivatives, mostly due to their undoubtedly favorable properties.

References

1. International Market Analysis Research and Consulting Group (2010) Global Biopharmaceutical Market Report (2010–2015).

2. Rader, R.A. (2008) (Re)defining biopharmaceutical. Nat. Biotechnol., 26, 743–751.

3. Orive, G., Gascon, A.R., Hernandez, R.M. et al. (2004) Techniques: new approaches to the delivery of biopharmaceuticals. Trends Pharmacol. Sci., 25, 382–387.

4. Jorgensen, L. and Nielson, H.M. (2009) Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines, Wiley, Chichester, West Sussex.

5. Rouget, C. (1859) Des substances amylacées dans les tissus des animaux, spécialement des Articulés (chitine). C. R. Hebd. Séances Acad. Sci., 48, 792–795.

6. Hoppe-Seyler, F. (1894) Ueber chitin und cellulose. Ber. Dtsch. Chem. Ges., 27, 3329–3331.

7. Machida, Y. and Nagai, T. (1989) Chitin/chitosan as pharmaceutical excipients, in Topics in Pharmaceutical Sciences (eds D.D. Breimer, D.J.A. Crommelin, and K.K. Midha), Fédération Internationale Pharmaceutique, The Hague.

8. Knapczyk, J., Krówczynski, L., Krzek, J. et al. (1989) Requirements of chitosan for pharmaceutical and biomedical application, in Chitin and Chitosan: Sources, Chemistry, Biochemistry, Plysical Properties and Applications (eds G. Braek-Skjåk, T. Anthonsen, and P. Sandford), Elsevier, London.

9. Illum, L. (1998) Chitosan and its use as a pharmaceutical excipient. Pharm. Res., 15, 1326–1331.

Acknowledgments

The editors would like to express their deepest gratitude to all the authors for accepting the challenge of writing this work. Also, a special word of appreciation is due to Professor María José Alonso for kindly accepting our invitation to write the foreword, and to everyone at Wiley who assisted in the production of this book.

Part One

General Aspects of Chitosan

Chapter 1

Chemical and Technological Advances in Chitins and Chitosans Useful for the Formulation of Biopharmaceuticals

Riccardo A. A. Muzzarelli

Professor Emeritus of Enzymology, University of Ancona, Ancona, Italy

1.1 Introduction

Chitin is the first polysaccharide discovered (1811): its bicentennial has been celebrated in a review article by Muzzarelli et al. [1] that traces the origin of the modern carbohydrate polymers science. In a more recent time, chitosans and their derivatives have been studied for formulations that enhance the absorption of macromolecular biotherapeutics (peptides, protein therapeutics and antigens, as well as plasmid DNA) and for the preparation of particulate drug-targeting systems. The number of yearly published papers dealing with this topic during the period 2000–2009 has been growing at the following impressive rate: 90, 110, 120, 150, 245, 320, 420, 470, 670, and 705. Some review articles are cited here for readers seeking complementary information. Kean and Thanou [2] published an overview about the biodegradation, biodistribution, and toxicity of chitosan-based delivery systems as well as the current status of chitosan drug formulations and underlined that, despite the high number of published studies, chitosan is not approved by the US Food and Drug Administration for any product in drug delivery. Nevertheless, chitosan is used as a generally regarded as safe (GRAS) material. It was explained that when a hydrophobic moiety is conjugated to a chitosan unit, the resulting amphiphile forms self-assembled as nanoparticles that encapsulate a quantity of drugs and deliver them to specific sites. Chemical attachment of drugs to chitosan throughout a functional linker may also produce useful prodrugs, exhibiting the appropriate biological activity at the target site.

The advanced development of chitosan hydrogels has led to new drug delivery systems that release drugs under varying environmental stimuli. The development of intelligent drug delivery devices requires a foundation in the chemical and physical characteristics of chitosan-based hydrogels, as well as the therapeutics to be delivered. In their review article, Bhattarai [3] reported on the developments in chitosan hydrogel preparation and defined the design parameters in the development of physically and chemically cross-linked hydrogels. Carreira [4] addressed smart polymers derived from chitosan, including particulate carrier systems, hydrogels, and film-based materials that are responsive to stimuli such as temperature and pH, and summarized recent developments in graft modification of chitosan by living radical polymerization.